May 20, 1959
COMMUNICATIONS TO THE EDITOR
2597
(1-cyclopenteny1)-piperidine to produce a 74% dichloride and cleavage of the B-C bond with hyyield of mixed 2,3,4,5,6,7- and 2,3,4,4a,5,6,- drogen peroxide gave p- and m-cresol in a 3 :2 molar hexahydro-1-methyl-1H-1-pyrindine,b.p. 65-66' ratio (infrared determination) ; no o-cresol was (6 mm.), confirmed by analysis (calcd. for CgH15N: present in detectable quantities. When prepared C, 78.77; H, 11.02. Found: C, 78.71; H, 11.19) a t 35") the ratio of pura to meta isomers in tolyland by infrared absorption of the free base and of dichloroborane was about 4.6:l. The aryldithe perchlorate salt, m.p. 215-217'. Similarly, chloroboranes formed from the isomeric xylenes N-methyl-3-bromopropylamine hydrobromide re- a t 35" were: meta, 3,5-xylyl- with trace amounts of acts with 1-(1-cyclohexeny1)-piperidineto produce a 2,5-xylyl-; ortho, 3,4-xylyl-; and para, 2,5-xylyl-. 73% yield of mixed 1,2,3,4,5,6,7,8- and 1,2,3,4,4a, Mesitylene at 140O gave largely 2,5-xylyldichloro5,G,7-octahydro-1-methylquinoline, b.p. 82-84 borane (-15% yield) with a small amount of the (6 mm.), confirmed by infrared studies and by 2,4- isomer. At 35O, mesitylene reacted to form catalytic reduction to cis-l-methyldecahydroquino- traces of mesityldichloroborane. Durene was inline (picrate salt, m.p. 199-201 O, reported m.p. active a t 140'. At 30") naphthalene and also 199-200°,3anal. calcd. for C ~ O H I ~ N . ( N O Z ) $: ~ ~biphenyl H ~ ~ H appeared to give more than one type of C,50.25; H,5.80. Found: C, 50.35; H,5.71). arylboron derivative. Further studies are under way to determine the The distribution of isomers in this synthesis of scope of this reaction. arylboranes is comparable to that in FriedelCraft reactions that are run in the presence of alu(3) M. Ehrenstein and W. Bunge, Be*., 67, 1715 (1934). minum chloride? Accordingly, it is suggested that P A R K E , DAVISAND COMPANY DETROIT32, MICHIGAN ROBERT F. PARCELLthe active species in this synthesis may be BCIz+ RECEIVED FEBRUARY 16, 1959 or ArH.BCl2+. Such species would be stabilized by the formation of the A1C14- anion, and reaction of the cation complex with the active aluminum SYNTHESIS OF ARYLDICHLOROBORANES surface would then produce the ArBCI2 compound. Sir: The aspect of reaction mechanism is being investiWe have found a simple and direct synthesis of gated. aryldichloroboranes from boron trichloride and (5) Alumimm chloride is a co-product in this synthesis of arylboron aromatic hydrocarbons. chlorides. These halides were prepared by charging a stain- CONTRIBUTION No. 530 FROM THE less steel-lined pressure vessel (400 ml. internal CENTRAL RESEARCH DEPARTMEST, EXPERIMENTAL STATION capacity) with 100-125 g. of aromatic hydrocarbon, E. I. DU PONTDE NEMOURS AXD COMPASY, DELAWARE E . L. MUETTERTIES 2-30 g. of aluminum powder, 0.1 g. of aluminum WILMINGTON, RECEIVED FEBRUARY 17, 1959 chloride, iodine, or methyl iodide, and 60 g. of boron trichloride2 and heating the vessel, under autogenous pressure and with agitation to 120- O N THE MECHANISM OF FATTY ACID SYNTHESIS' 150" for 5-60 min. or to 30-50°3 for 24-48 hours. Sir : The product, usually a liquid slurry, was filtered that the first step Recently we have and the filtrate was distilled. In the case of in fatty acid synthesis is the carboxylation of benzene, the conversion to purified C8H5BCl2 acetyl c o i l to malonyl CoA catalyzed by the biotin ranged from 60 to 72%, b.p. 95" (48 mm.). Anal. containing Rlgo fraction in the presence of ATP Calcd. for Ca&BC12: C, 45.38; H, 3.17; B, 6.79; and Mn++. C1, 44.66. Found: C, 45.87; H, 3.54; B, 7.39; Malonyl Co-4 readily is converted to palmitate C1, 44.31. Variations in the C,H, to BC1, ratio in the presence of R2g3c and TPNH.2 This conversion had no significant effect on the nature of the prod- can be followed spectrophotometrically or isoucts, and there was no evidence for the formation of topically. The addition of acetyl Co-4 will signifi(C6&)2BC1 or C&(BC&)z. Polysubstitution in cantly increase the rate and extent of synthesis of the aromatic nucleus undoubtedly is unfavorable palmitate. Furthermore, a significant amount of because the strongly electronegative BCl2 group C14-acetyl CoA is incorporated into palmitate when deactivates the ring..' unlabeled malonyl CoA is used (Table I). The Tolyldichloroborane was obtained from toluene amount of label introduced into palmitate corin 60% conversions a t 140'. Hydrolysis of the responds to about one eighth of the total amount of (1) The classical methods for the preparation of aryldihaloboranes "CZ units" converted to palmitate (measured by have been discussed in a recent review by hl. F. Lappert, Chem. Rev.., TPNH oxidation). Unlabeled acetaldehyde does 66, 1049 (1956). E. Pace (Atli A c c a d . Lincei, 10, 193 (1929)) reported the synthesis of C6HaBCIz from benzene and boron trichloride over not reduce the amount of CI4-acetyl CoA incorpalladium biack a t 5OD-1500~. T h e Pace synthesis has been studied porated into palmitate and acetaldehyde is not by W. L. Ruigh, el nl. (WADC Technical Report 55-26, P a r t s 111-IV formed by the enzymic reduction of acetyl CoA (1956), P.B. Nos. 121,374 and 121,718. U. S. Dept. of Commerce, by TPNH.4 Not only acetyl CoA but also C14Washington, D. (2.). They found that, with charcoal-supported palladium catalysts, the yields were variable, probably due to sensitivity butyryl coL4 and C14-octanoyl CoA can be inof the catalyst t o poisons. corporated into palmitate in presence of malonyl (2) Boron tribromide and triiodide also proved operable, b u t boron CoA. trifluoride did not react under these conditions. (3) In one experiment with benzene, an exothermic reaction set in a t 3' and the internal temperature flashed t o 120'. A 6G'30 conversion to CsHbBCIz was obtained. Variations in reaction rate are attributed to variations in the activity of the aluminum surface. (4) The BClr group should be a t least as effective as CI in deactivating the ring, a n d chlorobenzene itself was found to be inert to the B C l r A l reagents a t 50°.
(1) This work was supported in p a r t by several grants: 20-88 and RG-5873. Division of Research Grants ( N I H ) ; H-2236(C3), National Heart Institute ( N I H ) ; G-3227, National Science Foundation; and AEC Contract AT(l1-1)-64, Project 4. (2) S. J Wakil, TEISJOURNAL, 80, 6465 (1958). (3) S. J. Wakil and J. Ganguly, fled. Proc., 18, 346 (1959). (4) R. 0. Brady, P?oc.N o t . A c a d . Sci., 44, 993 (1958).
2598
COMMUNICATIONS TO THE EDITOR TABLE I Additions
TPNH oxidized (mrmoles)
CL4-substrate incorporated into palmitate (mrmoles)
Sone 18.0 .. l-C'4-acetyl co.4 (12 mpmoles) 32.2 1.80 same acetaldehyde (1000 mpmoles) 32.2 1.90 l-C"-acetate (320 mpmoles) 18.0 0.00 2-Cl4-malonate (1000 mpmoles) 18.2 0.00 l-C14-butyryl CoA (30 nifixnoles) 18.2 1.10 1-C14-octanoylCoA (50 mpmoles) 20.0 3.00 Each cuvette contained 20 wmoles of potassium phosphate buffer pH 6.5, 50 mpmoles of T P S H , 50 mpmoles of synthetic unlabeled monoma1on)-1 COX, other substrates as indicated, 2000pg. of RzRoand H20 to 0.4 nil. Incubated ftrr 10 min. a t 38 .
Vol. 81
gation has revealed that this reagent readily converts ketones to P-keto acids (eq. 1). Equally important from a practical standpoint is our finding
+
1
I
1 R'
0
I'
8 ~l
R-C-CH-C-OH
R"
that the intermediate magnesium salts of P-keto acids (I) may be alkylated in situ. Thus the path RzBo,as prepared, does contain an enzyme which indicated by eq. 2 is experimentally a simple method decarboxylates malonyl CoA to COZ and acetyl for the alkylation of ketones. CoA (as measured by the enzymatic formation of Treatment of acetophenone with 3-4 molar citrate). This would explain why malonyl CoA in equivalents of hlMC in dimethylformamide a t the absence of added acetyl CoA can form palmitate 110-120" for one hour, and then acid hydrolysis, in the presence of Rz,, and T P K H (Table I). furnished a 68% yield of benzoylacetic acid, m.p. Rz,,does not contain enoyl hydrase, P-hydroxyacyl 99-100" dec. (reported,2 100" dec.). 1-Indanone dehydrogenase or thiolase nor does it catalyze the was converted in 91% yield by the same technique oxidation of T P N H by acetyl CoA, acetoacetyl to 1-indanone-2-carboxylic acid, m.p. 100-101 CoA, P-hydroxybutyryl CoA, crotonyl CoA, butyryl dec. ( r e p ~ r t e d98-100" ,~ dec.). Co& A2-3-hexenoyl CoA and octanoyl CoA. The Cyclohexanone (1.82 g., 0.0186 mole) was heated oxidation of T P N H in this system requires the with 80 ml. of 1.94 Ad MMC solution a t 120-130° combined presence of malonyl CoA and some for 6 hours. After hydrolysis the crude product unsubstituted fatty acyl CoA (cz, Car ( 2 6 etc.). was extracted into ether, dried, and treated with None of the substituted intermediates of the P- ethereal diazomethane. Crystallization from methoxidation sequence can replace these fatty acyl anol gave 1.90 g. (48%) of dimethyl cyclohexanoneC o 9 esters. These observations suggest a pos- 2,6-dicarboxylate, m.p. 139-140" (reported4 n1.p. sible mechanism of fatty acid synthesis 142-143 ") identical with an authentic specimen.' Biotin-containing Xlternatively the free diacid, m.p. 123" dec., CHzCOCo.4 COI + -1TP > neut. equiv., 99.5 (reported6 m.p. 120-140° dec.) R1w could be isolated by crystallization from etherHOOCCHzCOCoX petroleum ether. Evidence for the importance R?,, of the coordinating properties of magnesium in CH~COCCJA f HOOCCH2COCo-1 -+ these reactions may be seen by comparing this TPNH CHaCOCH(COOH)COCo.-~ result with that obtained7 by treatment of cyclo-H i 0 hexanone with sodium ethyl carbonate. CHaCHOHCH( COOH)COCO.\ 1-Tetralone was treated with MMC solution at TPNH 120-130" for one hour, and to the cooled mixture CHaCH==C( C0OH)COCorZ an excess of benzyl bromide was added. Heating CHaCH2CH( C00H)COCo-1 + on the steam-bath for 6 hours, acid hydrolysis, CH~CHZCHICOCOX 4- C 0 2 and decarboxylation provided a 72% yield of 2The butyryl CoA formed can condense with another benzyl-1-tetralone, b.p. 150-155°(0.4 mm.), ni.p. molecule of malonyl CoA with the formation of the 51-53' (reported,8b.p. 1 7 6 O ( l mm.), m.p. 53-54'), When acetophenone was heated with M L l C P-ketodicarboxylic acid as indicated above. (4 equiv.) as described above, followed by methyl (5) Postdoctoral Trainee of t h e Institute for Enzyme Research, iodide (3 equiv.), a 74y0 yield of isobutyrophcUniversity of Wisconsin. none was obtained after decarboxylation. PropioISSTITUTEFOR ENZYME RESEARCH UNIVERSITY OF WISCONSIS SALIH J. WAKIL phenone was not isolated, even when less than two MADISON, WISCON~IX J. GANGULYSequivalents of alkylating agent was used. EviRECEIVED MARCH 24, 1959 dently the chelate salt froin 2-benzoylpropionic acid (I, R = C&, R' = CHs), which would be CHELATION AS A DRIVING FORCE I N SYNTHESIS. formed rapidly from the initial alkylation product
+
[
-
-1
__f
11.
USE OF MAGNESIUM METHYL CARBONATE I N THE CARBOXYLATION AND ALKYLATION OF KETONES
Sir: A previous communication1 described the use of magnesium methyl carbonate (MMC) for the carboxylation of nitroparafins. Further investi( 1 ) If,Stiles and H. I.. Finkbeiner. THISJ O U R X A L , 81, 205 ( I U 5 Y ) .
( 2 ) 13. Beckmann and T. Paul, .4,;1~.,266, 1 (1591). ( 3 ) R H. Wilep and P. H. Hobson, THIS J O U R N A L , 71, 342Y (l94iJ). ~ 4 )F. l?.Blickr and F. J. McCarty, J . O J ' ~CIicwz., . in press. ( 5 ) Sample provided through the courtesy < I f Drs. R. E. Ireland t r n d 1'. W. Schiess. ~ , L). K . V .iter[, J . C l i e ~ i .?,IC. ~ . , Z:jtI J . Q' C i ~ o kJ, . 1) I , u u d o ~aiid
17) J. I. Jones, Chriii. apid l i d . (Loiidoiz), 228 (lU28). ( 8 ) \V.Borsche, I' Hufmann and M K u h n , 21nn., 554, 23 (1913).
